Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant transformation of cells is associated with changes in gene expression. Gross alterations in chromatin organization may be involved in such gene dysregulation, as well as the involvement of specific transcription factors. Specialized genomic DNA segments that exhibit high affinity to the nuclear matrix in vitro have been designated as matrix/scaffold attachment regions (MARs/SARs). MARs are postulated to anchor chromatin onto the nuclear matrix, thereby organizing genomic DNA into topologically distinct loop domains that are important in replication and transcription. In support of this notion, MARs often colocalize or exist in close proximity to regulatory sequences including enhancers. Base unpairing regions (BURs) are typically 100-150 bp regions within MARs, possess an intrinsic propensity to unwind under negative superhelical strain, and are considered to be hallmark of MARs. To investigate a potential mechanism that could lead to significant alterations in gene expression in cancer cells, this review focuses on a group of chromatin-associated proteins that specifically recognize double stranded BURs. Several important proteins have been identified from cancer cells as BUR-binding proteins, including poly (ADP-ribose) polymerase (PARP-1), Ku autoantigen, SAF-A, HMG-I(Y), nucleolin and p53. Many of these proteins are dramatically upregulated in malignancy of the breast. Increase in the amount of these BUR-binding proteins, some of which are known to interact with each other, may not only provide an architectural core but also recruit functional multi-molecular complexes at the base of chromatin loops to affect multiple distant genes. Experimental strategies by which these proteins can be exploited as carcinoma-specific diagnostic markers and as targets for antineoplastic therapy are discussed.
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PMID:Chromatin (dis)organization and cancer: BUR-binding proteins as biomarkers for cancer. 1218 16

Malignant transformation was demonstrated in UROtsa cells following 52-weeks of exposure to 50 nM monomethylarsonous acid (MMA(III)); the result was the malignantly transformed cell line, URO-MSC. URO-MSC cells were used to study the induction of DNA damage and the alteration of DNA repair enzymes in both the presence of MMA(III) [URO-MSC(+)] and after subsequent removal of MMA(III) [URO-MSC(-)] following chronic, low-level exposure. In the presence of MMA(III), URO-MSC(+) cells demonstrated a sustained increase in DNA damage following 12-weeks of exposure; in particular, a significant increase in DNA single-strand breaks at 12-weeks of exposure consistently elevated through 52 weeks. The persistence of DNA damage in URO-MSC cells was assessed after a 2-week removal of MMA(III). URO-MSC(-) cells demonstrated a decrease in DNA damage compared to URO-MSC(+); however, DNA damage in URO-MSC(-) remained significantly elevated when compared to untreated UROtsa and increased in a time-dependent manner. Reactive oxygen species (ROS) were demonstrated to be a critical component in the generation of DNA damage determined through the incubation of ROS scavengers with URO-MSC cells. Poly (ADP-ribose) polymerase (PARP) is a key repair enzyme in DNA single-strand break repair. URO-MSC(+) resulted in a slight increase in PARP activity after 36-weeks of MMA(III) exposure, suggesting the presence of MMA(III) is inhibiting the increase in PARP activity. In support, PARP activity in URO-MSC(-) increased significantly, coinciding with a subsequent decrease in DNA damage demonstrated in URO-MSC(-) compared to URO-MSC(+). These data demonstrate that chronic, low-level exposure of UROtsa cells to 50 nM MMA(III) results in: the induction of DNA damage that remains elevated upon removal of MMA(III); increased levels of ROS that play a role in MMA(III) induced-DNA damage; and decreased PARP activity in the presence of MMA(III).
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PMID:Persistence of DNA damage following exposure of human bladder cells to chronic monomethylarsonous acid. 1969 19

Malignant transformation may occur in the background of post-translational modification, such as ADP-ribosylation, phosphorylation and acetylation. Recent genomic analysis of ADP-ribosylation led to the discovery of more than twenty ADP-ribosyltransferases (ARTs), which catalyze either mono- or poly-ADP-ribosylation. ARTs catalyze the attachment of ADP-ribose to acceptor molecules. The ADP-ribose-acceptor bond can then be cleaved by a family of hydrolases in a substrate-specific manner, which is dependent on the acceptor and its functional group, e.g., arginine (guanidino), serine (hydroxyl), aspartate (carboxyl). These hydrolases vary in structure and function, and include poly-ADP-ribose glycohydrolase (PARG), MacroD1, MacroD2, terminal ADP-ribose protein glycohydrolase 1 (TARG1) and ADP-ribosyl-acceptor hydrolases (ARHs). In murine models, PARG deficiency increased susceptibility to alkylating agents-induced carcinogenesis. Similarly, by cleaving mono-ADP-ribosylated arginine on target proteins, ARH1 appears to inhibit tumor formation, suggesting that ARH1 is a tumor-suppressor gene. Although ARH3 is similar to ARH1 in amino acid sequence and crystal structure, ARH3 does not cleave ADP-ribose-arginine, rather it degrades in an exocidic manner, the PAR polymer and cleaves O-acetyl-ADP-ribose (OAADPr) and the ADP-ribose-serine linkage in acceptor proteins. Under conditions of oxidative stress, ARH3-deficient cells showed increased cytosolic PAR accumulation and PARP-1 mediated cell death. These findings expand our understanding of ADP-ribosylation and provide new therapeutic targets for cancer treatment. In the present review, research on ARH1-regulated tumorigenesis and cell death pathways that are enhanced by ARH3 deficiency are discussed.
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PMID:Emerging roles of ADP-ribosyl-acceptor hydrolases (ARHs) in tumorigenesis and cell death pathways. 3026 46